TW-37 is a novel nonpeptide inhibitor to recombinant Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.29 μM, 1.11 μM and 0.26 μM, respectively.

Bcl-2 (B-cell lymphoma 2) is encoded by the Bcl-2 gene and is the
first identified member of a large family of apoptosis regulatory
proteins (Bcl-2 family) that derives its name from the B-cell lymphoma
2, as it is the second member of a variety of proteins initially
described in the t(14;18) chromosomal translocation in human follicular
B-cell lymphomas. Bcl-2 contains four Bcl-2 homology domains (BH1-BH4)
that mediate the formation of homodimer and heterodimer with relative
proteins such as Bax, Bad, Bak and Bcl-xL, and a trans-membrane (TM)
domain that mediates insertion into the outer membrane of the
mitochondria and the endoplasmic reticulum. Bcl-2 proteins are generally
integrated within the outer mitochondrial membrane (OMM), and may also
be in the cytosol or ER membrane. The Bcl-2 and other antiapoptotic
members of the Bcl-2 family preserve the outer mitochondrial membrane
(OMM) integrity, thus inhibiting the mitochondrial signaling pathway of
apoptosis, by complex interactions with the proapoptotic Bcl-2 proteins
such as Bax, Bak, Bim, Puma and tBid. [1][2]

Bcl-2 suppresses apoptosis in response to a broad range of stress
stimuli, including those frequently encountered during tumor
development, such as oncogene activation, DNA damage, hypoxia (oxygen
deprivation), loss of appropriate growth signals and anoikis (loss of
cell attachment). In healthy cells, Bax and Bak are kept in check by the
pro-survival Bcl-2 family members and the binding of BH3-only proteins
unleashes Bax/Bak. Bcl-2 is also critical for the survival of renal
epithelial stem cells during embryogenesis, melanocyte progenitors and
mature B and T lymphocytes. Bcl-2 over-expression accelerates
Eu-myc-induced lymphomagenesis, but loss of endogenous Bcl-2 does not
prevent or delay Eu-myc-induced B lymphoma development. Bcl-2 proteins
also constitutively binds to Beclin-1, and its dissociation through
post-translational modification of Beclin-1 and/or Bcl-2 proteins such
as phosphorylation by JNK1, or direct competition for the Bcl-2 BC
groove by another BH3-only protein such as Bad, may be sufficient to
induce autophagy, leading to the suggestion that autophagy and apoptosis
are mechanistically linked. Single-site phosphorylation at Serine 70
(S70) is required for the antiapoptotic function of Bcl-2, and multisite
phosphorylation at Threonine 69, S70, and S87 has been reported to
inactivate Bcl-2. Phosphorylation of Bcl-2 has been shown to enhance
activity to allow response to extracellular growth-factor-mediated
signals. [1][2][3]
In addition, Bcl-2 is over-expressed in human follicular centre
B-cell lymphoma; high levels of Bcl-2 are also detected in significant
numbers of chronic lymphocytic leukaemia (CLL), DLBCL and mantle cell
lymphoma, as well as in certain solid tumours(brain, breast and lung).
The upregulation of Bcl-2 in CLL and other cancers has been attributed
to the hypo-methylation of the Bcl-2 promoter or, possibly more
importantly due to hemizygous or homozygous loss of the micro RNAs
(miRs) 15a and 16-1 that negatively regulate Bcl-2. The dysregulated
Bcl-2 proteins in cancer can lead to increased survival of abnormal
cells, which are thought to be involved in resistance to conventional
cancer treatment. Mice that constitutively express both Myc and Bcl-2
transgenes develop lymphoblastic leukaemia with high incidence, while
shut-down of the inducible Bcl-2 transgene in lymphoma-burdened
bi-transgenic mice results in tumor regression and significantly
prolonged animal survival in many cases, indicating that inactivation of
Bcl-2 constitutes a promising new approach to cancer therapy. Small
molecule mimetics of BH3-only proteins that can directly target
pro-survival Bcl-2 family members are being developed as a novel
therapeutic approach. ABT-737 and the closely related orally
bioavailable ABT-263, belong to the BH3 mimetic small molecule
inhibitors, targeting Bcl-2 and Bcl-2-related proteins such as Bcl-xL
and Bcl-w, therefore promoting tumor regression in murine
xeno-transplanation models of certain human lymphomas or small cell lung
carcinomas and in primary patient-derived follicular lymphoma cells.
[1][4]

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